The viral envelope proteins HA1 and HA2 play critical roles in influenza entry. HA2 mediates fusion of the viral and cellular membranes, thereby allowing entry of the influenza genetic material. The guiding hypothesis is that structural domains of HA2 can serve as models of the larger domain present in vivo. The long-term goal of this research is to perform rationale drug design and high throughput screening by NMR spectroscopy for novel antivirals that are designed to disrupt HA2 function and hence influenza infection. The specific aims are: (1) Generate and characterize influenza HA2 constructs, from the well characterized 1968 H3 strain, that are amenable for biophysical characterizations and drug discovery by NMR spectroscopy; (2) Generate and characterize influenza HA2 constructs, from the 1918 HI strain responsible for the most deadly flu pandemic to date, that are amenable for biophysical characterizations and drug discovery by NMR spectroscopy; (3) The structure and dynamic properties of the most promising HA2 constructs will be determined by NMR spectroscopy. [unreadable] [unreadable] [unreadable]